Sunscreening dihydroxy-diphenylsulfone derivatives



PERCEN T TRANSMISSION May 25, 1955 c. A. FETSCHER ETAL 3,185,623

SUNSCREENING DIHYDROXYDIPHENYLSULFONE DERIVATIVES Filed March 18. 1960I00 l I {2,2-DIHYDROXY 5,5-

DICHLORO DIPHENYLSULFONE olll Ill 2710 2820 2940 3000 3080 3240 344036%)VCNTO-ZZOO WAVELENGTH (N ANGSTROMS CHARLES AlFETSCHER STANLEYLIPOWSKI ATTORNEY United States Patent i 3,185,628 SUNSCREENINGDIHYDRGXY-DEPHENYL- dULFONE DEREVATHVES Charles A. Fetscher, ShortHills, and Stanley Lipowslri,

Newark, N..ll., assigners to Nopco Chemical Company,

Newark, NJL, a corporation of New Jersey Filed Mar. 18, 1960, Ser. No.15,88tl 11 (Iiaims. (Cl. 167-90) This invention relates to cosmeticpreparations useful for protecting the skin against sunburn. Moreparticularly, this invention relates to cosmetic preparations whichprotect the skin against burning when exposed to ultraviolet lightradiation While at the same time permitting tanning of the skin.

It is known that ultraviolet radiation is responsible for both tanningand burning of the skin. This is because the portion of actinicradiation designated as ultraviolet light radiation actually is adistribution of radiation energy varying in wave length from 2800 A. to4000 A. Within this range, the radiation of wave lengths of between 2800A. and 3150 A., referred to as short wave ultraviolet radiation, islargely responsible for sunburn or erythema which is harmful to theskin. On the other hand, radiation having wave lengths between 3150 A.and 3650 A., referred to as long wave ultraviolet radiation, bringsabout healthful tanning with very little erythemal eifect. Hence, topermit successful tanning of the skin, a number of cosmetic preparationshave been developed for the purpose of filtering out or screening outharmful short-wave ultraviolet radiation. However, many of thesecompositions suffer from a number of disadvantages. For example, many ofthese compositions suffer from inadequate selectivity. That is, althoughthey prevent erythema, they also prevent tanning. Also, many of thesepreparations undergo a chemical change of the active ingredient whenapplied to the skin and exposed to ultraviolet radiation and air. Thisis accompanied not only by reduced efiectiveness of the preparation as asun screen, but also by undesirable staining of the skin and clothingwith the decomposition products.

Accordingly, it is an object of the present invention to preparecosmetic preparations which when applied to the skin selectively filterout and render harmless the burning ultraviolet radiation of wavelengths between 2800 A. and 3150 A. while at the same time transmit thelonger ultraviolet radiation of wave lengths in excess of 3150 A. sothat the skin can be successfully tanned without burning or erythema. Itis a further object to prepare cosmetic preparations which are stableand non-staining when applied to the skin and exposed to ultravioletradiation and air. Another object is to prepare cosmetic preparationswhich also do not lose their effectiveness when exposed to ultravioletradiation for relatively long periods of time. A still further object isto provide a method for obtaining a sun tan without sunburn. Otherobjects will become apparent from the detailed description given herein.It is intended however that the detailed description and specificexamples do not limit the invention but merely indicate preferredembodiments thereof since various changes and modifications within thescope of the invention will become apparent to those skilled in the art.

We have unexpectedly discovered that the above and as well as otherobjects have been successfully achieved by means of cosmeticpreparations of the nature of sun tan lotions, creams, oils and the likewhich contain as the effective ingredient alkyl and halogen derivativesof 2,2 dihydroxy diphenyl sulfone. It is known according to Fatent No.2,874,090, Klein, February 17, 1959; Patent No. 2,880,140, de Navarre,March 31, 1959, as well as others, that cosmetic preparations whichcontain as their effective ingredients compounds which have asresonating 3,185,628 Patented May 25, 1965 structures amide, amino,carboxyl, carbonyl, nitro and sulfonic acid groups do exhibitselectivity in their ultraviolet absorption-transmission properties.However, it was most unexpected to discover that the compounds of thepresent invention very completely absorbed the short wave lengthultraviolet radiation while at the same time transmitted the longer wavelengths in the absence of any of the above enumerated resonatingstructures. It was also unexpected to find that these compounds wereextremely stable during exposure to ultraviolet radiation and air.

Our class of 2,2 dihydroxy diphenyl sulfones are represented by thefollowing structure, viz:

OH OH wherein R can be halogen, or straight or branched chain saturatedaliphatic hydrocarbon substituents having from one to five carbon atomsand R can be hydrogen, halogen or straight or branched chain saturatedaliphatic hydrocarbon substituents having from one to five carbon atoms.The aliphatic hydrocarbon substituents can have a greater chain lengththan indicated above. However, the increase in carbon chain length tendsto dilute the absorbing function of the sulfone. Useful halogens arechlorine and bromine while useful straight and branched chain saturatedaliphatic hydrocarbon substituents are, e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, amyl and sec.

- amyl. Exemplary of these 2,2 dihydroxy diphenyl sulfones are:

2,2 dihydroxy 5,5 dimethyl diphenyl sulfone 2,2 dihydroxy 5,5, 6,6tetramethyl diphenyl sulfone 2,2 dihydroxy 4,4, 5,5 tetramethyl diphenylsulfone 2,2 dihydroxy 5,5 diethyl diphenyl sulfone 2,2 dihydroxy 5,5diisopropyl diphenyl sulfone 2,2 dihydroxy 5,5 ditertiary butyl diphenylsulfone 2,2 dihydroxy 5,5 di sec. amyl diphenyl sulfone 2,2 dihydroxy5,5 dichloro diphenyl sulfone In general, these 2, 2 dihydroxy diphenylsulfones can be prepared by reacting approximately two mols of a phenolhaving the formula wherein R and R nave the same designations heretoforegiven, with approximately one mol of sulfuric acid. Use ful phenols arep-cresol; p-chlorophenol; 3,4-dimethyl phenol, etc. The phenol andsulfuric acid, along with a solvent such as monochlorobenzene, arecharged into a reaction kettle and refluxed. Enough solvent is kept inthe system to maintain a good reflux. The amount of solvent necessaryvaries with the volume and shape of the equipment used and is adjustedaccording to conditions of operation. After about two mols of water havebeen removed azeotropically during reflux, the reaction mass is cooleddown, more water added and the solvent removed azeotropically. Theremaining material is washed with water at elevated temperatures. Thewater separates very easily as the upper layer and is easily removed bydecantation. Then methanol or any other solvent is added which dissolvesthe resinous by-products formed during the reaction, but does notdissolve the sulfone. In this manner, the sulfone separates out and whencooled down, the solution of resinousby-products is filtered off. Thefiltrate contains the solution of the resinous by-product while thesulfone stays behind. The sulfone is then washed and dried.

Useful 2,2 dihydroxy diphenyl sulfones can also be prepared by theoxidation of the appropriate 2,2 dihydroxy diphenyl sulfide. Thesesulfides are readily prepared by action of sulfur monochloride on thephenol.

The cosmetic preparations which contain these sulfones can be preparedin the following manner. The sulfone, or a mixture of sulfones can beadmixed with a vehicle with agitation or with agitation and heating ifnecessary. Since these sulfones are powerful absorbers,

' the cosmetic preparation need contain only a small concentration ofthe sulfone in order to filter out most of the short-wave skin burningultraviolet rays when the cosmetic preparation is applied topically as athin film to the skin. Generally, the concentration of the sulfone ormixtures thereof in the cosmetic preparation can be from about 2% toabout 8.5%, preferably about 4% to about 6% by weight of the total.Useful vehicles can be lotions, creams, oils, etc., i.e., any vehicle inwhich the active ingredient, i.e., the particular 2,2 dihydroxy diphenylsulfone or mixtures thereof can be dissolved, admixed or dispersed. Thevehicle thus serves as a carrier for the active ingredient so that itcan be uniformly applied in small quantities over the desired areas ofskin. Thus, the active ingredient can be dissolved in a water-ethanolsolution within the proportions heretofore given. Alternatively, theactive ingredient can be incorporated into any well known cosmetic basewithin the aforesaid proportions. Such bases can contain mineral oil,glycerine, lanolin, fatty acids, fatty acid esters, emulsifiers whereneeded, gums, etc. Ancillary ingredients such as colors,

perfumes and preservatives can be present in small 7 amounts, i.e.,generally less than about 1% by weight EXAMPLE I 2,2 dihydroxy 5,5dimethyl diphenyl sulfone 216 parts of p-cresol, 100 parts of sulfuricacid (98%) and 50 parts of monochlorobenzene were charged into areaction kettle. The resulting mass was stirred and heated untilrefluxing started. The vapor mixture leaving the kettle which containedwater and monochloro benzene was condensed and allowed to settle. Thewater layer separated from the chlorobenzene layer and the latter wasreturned to the reaction kettle. Refluxing started at a temperature ofabout 140 C. after which the temperature was gradually raised to 180 C.Additional monochlorobenzene was added as needed to maintain a goodreflux. After 32 parts of water were removed azeotropically from thereaction mass, the reaction mass was cooled down to 120 C. Fifty partsof water were then added and the solvent boiled off azeotropically. Thereaction mass developed into an orange colored paste which was washedthree times with 200 parts of water, each time at 60 C. The wash waterseparated very easily as the upper layer and was easily removed bydecantation from the reaction mass. 250 parts of methanol were thenadded to the washed paste. The resin formed during the reactiondissolved in the methanol forming a green-brown colored solution whilethe sulfone separated from the solution as a cream powder. After coolingdown to 8 to 10 C. the material was filtered and washed with methanoluntil the filtrate was clear, i.e., water-white. The sulfone was driedat 105 C. The product which was 2,2 dihydroxy 5,5

, 4 dimethyl diphenyl sulfone was a light cream colored solid having asharp melting point at 205 C. A yield of 34% of the theoretical wasobtained.

7 EXAMPLE II 2,2dihydr0xy 5,5 dichllon'o diphenyl sulfone 257 parts ofp-chlorophenol, parts of sulfuric acid (98%) and 60 parts ofmonochlorobenzene were mixed together and heated with stirring. Thewater formed during the reaction was removed azeotropically in the samemanner as in Example I. However, the temperature was raised gradually to200 C. After 34 parts of water were removed from the reaction mass, allof the chlorobenzene which distilled over with the water was returned tothe reaction vessel and 40 parts more of chlorobenzene were added. Thereatcion mass was cooled down to 20 C. and allowed to stand overnightduring which time crystallization occurred. The crystalline material wasfiltered, washed with chlorobenzene and then with hot water and finallydried at C. The product which was 2,2 dihydroxy 5,5 dichloro diphenylsulfone was a white solid, having a melting point of 188 to 190 C. Theyield was 48% of theoretical.

EXAMPLE III 2,2 dihydroxy 4,4,5,5 tetramethyl diphenyl sulfone 244 partsof 3,4 dimethylphenol were melted at 70 C. and 100 parts of sulfuricacid (96%) were added. The

temperature was allowed to rise to 100 C. and kept at' 100 C. for 15minutes. The temperature was again raised, this time to C., and kept for15 minutes at 120 C. 100 parts of monochlorobenzene were then added tothe reaction mass and the temperature raised gradually to 185 C. Thewater formed during reaction was removed azeotropically. After 32 partsof Water were removed, the reaction mass was cooled down to 120 C.,water added and the solvent removed azeotropically. Some unreacted 3,4dimethyl phenol distilled over with the water-chlorobenzene vapors. Thewater remaining in the reaction vessel was siphoned off and theresulting red reaction mass was dissolved in 750 parts of methanol. Thissolution was then cooled down to 0 C. The sulfone separated and wasfiltered off, washed with cold methanol and dried under vacuum. Theproduct which was 2,2 dihydroxy 4,4',5,5' t'etramethyl diphenyl sulfonewas a solid having an off-white color and having a melting point of 238C. to 240 C. A yield of 40% of theoretical was obtained.

EXAMPLE IV 2,2 dihydroxy 5,5 dibutyl diphenyl sulfone 300 parts ofp-tertiary butyl phenol were dissolved in 750 parts of carbon disulfideat reflux temperature. After the addition was completed, the resultingsolution was cooled down to 20 C. and parts of sulfur monochloride wereslowly added while maintaining the temperature at 20 to 25 C. by coolingthe reaction mass. During the addition, heavy fumes of hydrogen chlorideescaped. After all of the sulfur monochloride was added, the reactionmass was heated and refluxed at about 50 C. for 30 minutes. In thismanner, 2,2 dihydroxy 5,5 dibutyl diphenyl sulfide was formed.Thereafter, the carbon disulfide was removed by vacuum distillation.

The 2,2 dihydroxy 5,5 dibutyl diphenyl sulfide was then dropped intocold water. After the water was decanted oil", the sulfide was washedtwice with water, taken up with ether, dried with sodium sulfate andfinally the ether removed by evaporation. The sulfide was then dissolvedin 750 parts of acetic acid after which parts of hydrogen peroxide (50%by weight aqueous solution) were slowly added to the solution whileusing intermediate cooling to maintain the temperature at 90 to 95 C.

The resulting product was dropped into cold water, taken up with ether,dried with sodium sulfate and finally the ether evaporated in vacuum.The product which was 2,2 dihydroxy 5,5 dibutyl diphenyl sulfone was aheavy .yellow sirup which solidified at room temperature. A

yield of 50% of theoretical was obtained.

EXAMPLE V EXAMPLE VI A 0.004% by weight solution of 2,2 dihydroxy 5,5dimethyl diphenyl sulfone in isopropanol was prepared and theultraviolet spectra of the solution was determined and recorded with aBeckman Model DU quartz spectrophotometer. The resulting curve wasalmost the same as that obtained in Example V. The curve clearlydemonstrated the excellent selectivity of this material, i.e., it veryexcellently absorbs the short ultraviolet radiation which is responsiblefor burning or erythema of the skin while at the same time it transmitsthe longer ultraviolet rays which bring about tanning without burning.

EXAMPLE VII In this example, the compounds of Examples I, II and IIIwere made up into dilute solutions in isopropanol as the solvent and thepercent transmission of the ultraviolet as a function of wave length wasdetermined. The percent transmission of the total amount of incidenterythemal energy and the percent transmission of the total amount ofincident tanning energy was determined in the manner disclosed by Krepsin Proceedings of the Scientific Section of the Toilet GoodsAssociation, No. 23, May 1955. The data thus obtained are set forth asfollows:

Conce. Percent trans- Percent trans- Sulfone irom (percent mission oftotal mission of total weight) incident erythemal incident tanningenergy energy The above data clearly indicate that the sunscreencompositions of the present invention are highly effective. They aitordgood protection against erythema by absorbing a large percentage of theundesirable burning rays while at the same time permit optimum tanningby transmitting a large percentage of the desirable tanning rays.

EXAMPLE VIII In this example, several subjects were exposed toultraviolet light radiation and the effectiveness of the sulfonedetermined. The procedure was as follows.

A solution of 5.5 grams of 2,2 dihydroxy 5,5 dimethyl diphenyl sulfonein 94.5 gm. of ethyl alcohol (95%) was applied to the underside of theright forearm of six subjects in an area approximately 1 x 3".Contiguous areas were protected by application of surgical tape. Thetreated areas were exposed to the radiation of a Hanovia quartzultraviolet lamp for exactly 14 minutes. The distance from the exposedsurface of the arm to the burner was 12" and the radiation was filteredthrough a plate of Corex D glass. Under these conditions, a minimumperceptible erythema is produced on the average in about one minute whenthe skin is not protected. The following evaluations were made after 24hours.

2,2 dihydroxy Subject Complexion 5,5 dimethyl diphenyl sulfone N oerythema.

Do. Do. Do do Do. Female Light brunette- Do. Do Blnnde D0.

The following three examples illustrate several cosmetic preparationswhich contain various sulfones. Each of these preparations was found toprotect the skin from sunburn when applied to the skin and the thustreated skin exposed to strong sunlight for at least one hour. Nostaining of the skin or of adjacent clothing was observed.

EXAMPLE IX Percent by wt. Ethanol 50 Water 45 2,2 dihydroxy 5,5 dichlorodiphenyl sulfone 5 The above ingredients were mixed together withstirring to form the finished product. A portion of the product wasapplied to the skin which was exposed to strong sunlight for at leastone hour.

EXAMPLE X Percent by wt. White mineral oil 20 Propylene glycol 5Isopropyl myristate .Q. 5 Lanolin 1 Non-ionic emulsifier 1 3 2,2dihydroxy 5,5 dimethyl diphenyl sulfone 4 Water 62 The reaction productof octyl phenol and eight mols of ethylene oxide.

All of the materials except the water were mixed together and heated to70 C. Then the resulting mixture was added to the water which wasseparately heated to 70 C. Blending with vigorous agitation was carriedout to form a stable emulsion. A portion of the product was The abovematerials were mixed together and a portion of the resulting admixturewas applied to the skin and exposed to strong sunlight for at least onehour.

As the foregoing has shown, outstanding sunscreen compositions haveresulted from this invention. These compositions in a very excellentmanner when applied to skin, permit tanning of the skin withoutundesirable erythema. These compositions are further characterized bytheir stability during use. That is, their eifectiveness is not lostduring exposure to air and sunlight. Also in view of their stability,these compositions do not stain the skin and adjacent clothing withdecomposition products.

Having described our invention what we claim as new and desire to secureby Letters Patent is:

1. A method of screening out erythemal ultraviolet light radiationhaving a wave length of between about 2800 A. and 3150 A. from skinwhile at the same time permitting tanning of the skin which comprisestopically applying to human skin which is subject to sunburn a thin filmof a sunscreen composition containing (1) a sunscreen agent having theformula wherein R is selected from the group consist-ing of halogen andstraight and branched chain saturated aliphatic hydrocarbon substituentshaving from one to five carbon atoms and R is selected from the groupconsisting of hydrogen, halogen and straight and branched chainsaturated aliphatic hydrocarbon substituents having from one to fivecarbon atoms, said sunscreen agent further characterized by absorbingultraviolet light radiation having a wave length between about 2800 A.and 3150 A. and (2) a pharmaceutically acceptable vehicle for saidsunscreen agent, said sunscreen agent being present in said vehicle inan amount sufficient to screen out substantially all of said ultravioletlight radiation having a wave length of between about 2800 A. and 3150A. when applied to the skin in a thin film.

2. The method of claim 1 in which said sunscreen composition containssaid sunscreen agent in an amount of from about 2% to about 8.5% byweight of the total composition.

3. The method of claim 1 in which said sunscreen composition containssaid sunscreen agent in an amount of from about 4% to about 6% by weightof the total composition.

4. The method of claim 3 in which said sunscreen agent is 2,2dihydroxy5,5dimethy1 di henyl sulfone.

cosmetic lotion.

10. The method of claim 3 in which said vehicle is a cream.

11. The method of claim 3 in which said vehicle is an oil.

References Cited by the Examiner UNITED STATES PATENTS 2,290,294 7/42Riess 260-607 OTHER REFERENCES Chaix: Bulletin Societe Chimique deFrance, Quart. Serie, tome 53, Pt. 2, 1933.

Gump: J.A.C.S., vol. 67, February 1945, pp. 238-240.

J. of The Society of Cosmetic Chemists, 12:3, April I. fiir PracktischeChemie, N.F., Band 160, 1942, pp. 52-64.

J. Chem. Soc. London, 1949, p. 410.

Drug and Cos. Ind.,.October 1944, p. 472.

Gustavson: The Chem. of Tanning Processes, Academic Press, N.Y., 1956,pp. 202-206.

JULIAN S. LEVITT, Primary Examiner.

M. O. WOLK, FRANK CACCIAPAGLIA, JR.,

LEWIS GOTTS, Examiners.

1. A METHOD OF SCREENING OUT ERYTHEMAL ULTRAVIOLET LIGHT RADIATIONHAVING A WAVE LENGTH OF BETWEEN ABOUT 2800 A. AND 3150 A. FROM SKINWHILE AT THE SAME TIME PERMITTING TANNING OF THE SKIN WHICH COMPRISESTOPICALLY APPLYING TO HUMAN SKIN WHICH IS SUBJECT TO SUNBURN A THIN FILMOF A SUNSCREEN COMPOSITION CONTAINING (1) A SUNSCREEN AGENT HAVING THEFORMULA